Pancreatitis is an inflammation of the pancreas. It has various causes. Once the gland becomes inflamed, the condition can progress to swelling of the gland and surrounding blood vessels, bleeding, infection, and damage to the gland. Digestive juices become trapped and start “digesting” the pancreas itself. If this damage persists, the gland may not be able to carry out normal functions.
Pancreatitis may be acute (new, short-term) or chronic (ongoing, long-term). Acute pancreatitis is a common disease that causes significant morbidity and mortality. Either type can be very severe, and lead to serious complications. Chronic pancreatitis begins as acute pancreatitis. If the pancreas becomes scarred during the attack of acute pancreatitis, it cannot return to its normal state. The damage to the gland continues, worsening over time.
Acute pancreatitis usually begins soon after the damage to the pancreas begins. Attacks are typically very mild. Mild attacks may last for a short time and usually resolves completely as the pancreas returns to its normal state. Some people have only one attack, whereas other people have more than one attack. About 20% of cases however, are very severe. There are reports that more than 300,000 patients are admitted per year for pancreatitis in the United States, and about 20,000 of those patients die from the disease. Pancreatitis can occur in people of all ages, although it is very rare in children. Pancreatitis occurs in men and women, although chronic pancreatitis is more common in men than in women.
Alcohol abuse and gallstones are the two main causes of pancreatitis, accounting for 80%-90% of all cases. Pancreatitis from alcohol use usually occurs in patients who have been long-term alcohol drinkers for at least five to seven years. Most cases of chronic pancreatitis are due to alcohol abuse. Pancreatitis is often already chronic by the first time the person seeks medical attention (usually for severe pain). Gallstones form from a buildup of material within the gallbladder. A gallstone can block the pancreatic duct, trapping digestive juices inside the pancreas. Pancreatitis due to gallstones tends to occur most often in women older than 50 years of age.
The remaining 10%-20% of cases of pancreatitis have various causes, including the following: medications, exposure to certain chemicals, injury (trauma), as might happen in a car accident or a bad fall leading to abdominal trauma, hereditary disease, surgery and certain medical procedures, infections such as mumps (not common), abnormalities of the pancreas or intestine, or high fat levels in the blood. In about 15% of cases of acute pancreatitis and 40% of cases of chronic pancreatitis, the cause is never known.
High levels of triglycerides are associated with acute pancreatitis and considerable morbidity and mortality. In September of 2002, the National Institute of Health published its third report of the Expert Panel on Detection Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATPIII guidelines). Although the focus of this report is on LDL -cholesterol and HDL-cholesterol levels, it also provides guidance for treatment of patients having high triglyceride levels. The report adopted a classification for triglyceride levels: normal triglycerides: below 150 mg/dL, borderline-high triglycerides: between 150-199 mg/dL, high triglycerides: between 200-499 mg/dL, and very high triglycerides: ≧500 mg/dL. For all the groups the guidelines indicates that the primary aim of therapy is to reach the target goal for LDL cholesterol. For patients with borderline or high triglyceride level the guidelines recommend that treatment should focus on weight reduction, increased physical activity, treatment with LDL-lowering drugs, and if used with appropriate caution, nicotinic acid or fibrate can be added to achieve the non-HDL cholesterol goal by further lowering of VLDL cholesterol. The guidelines are clear that in those cases in which triglycerides are very high (≧500 mg/dL), that the initial aim of therapy is to prevent acute pancreatitis through triglyceride lowering. The guideline recommend that this approach requires very low fat diets, weight reduction, increased physical activity, and usually a triglyceride-lowering drug (fibrate or nicotinic acid).
Although fibrates are generally well-tolerated in most persons, they are associated with well-established side effects. All drugs in this class appear to increase the likelihood of cholesterol gallstones. In addition, because fibrates bind strongly to serum albumin, they may displace other drugs that bind with albumin. For example, fibrates displace warfarin from its albumin-binding sites, thereby increasing warfarin's anticoagulant effect. Fibrates are excreted primarily by the kidney; consequently, elevated serum levels occur in persons with renal failure and risk for myopathy is greatly increased. The fibrate gemfibrozil is a CYP3A4 substrate and as such inhibits the metabolism of some statins, including atorvastatin, lovastatin and simvastatin. This competition decreases rate of metabolism of the drugs resulting in their accumulation. This effect increases the risk for myopathy, which can lead to rhabdomyolysis. Fibrates also interfere with the metabolism of the protease inhibitors, indinavir, ritonavir, saquimavir and nelfinavir which are both substrates and inhibitors of CYP3A4. Gemcabene has been shown to have a low level of inhibition of CYP3A4, however in a drug-drug interaction study with simvastatin (a CYP3A4 substrate) showed no clinically relevant effect.
Dyslipidemia is common in persons with HIV infection on highly active antiretroviral therapy (HAART), the typical pattern includes elevated total cholesterol, LDL, and triglyceride, which may be markedly elevated. The hypertriglyceridemia appears to be related to the treatment with protease inhibitors. Treatment decisions in HIV treatment are complex and must include consideration of multiple potential drug-drug interactions in view of the selection of lipid-lowering drugs. Statins remain the most effective drugs for lowering LDL cholesterol however because fibrates and certain statins and protease inhibitors are CYP3A4 substrates, combination therapy can lead to increased levels of statin which are associated with an increased incidence of myopathy.
Nicotinic acid is also associated with side-effects. In persons with elevated serum glucose; nicotinic acid may worsen hyperglycemia and triglycerides may actually increase. Some patients treated with nicotinic acid develop severe liver toxicity.
There currently are no effective therapeutic treatments for the pancreatitis. Current treatments include giving antibiotics to treat or prevent infections, pain relievers, and changes in diet. Thus, in patients at risk for developing pancreatitis, e.g. with triglyceride levels ≧500 mg/dL. It is desirable to treat at risk patients prophylactically before pancreatitis occurs, or reoccurs, and also to treat patients with pancreatitis. Given the inadequacies of current treatment, there is a need for improved therapies for treating patients having high triglyceride levels.